About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

September 8, 2005

Muraglitazar's Turn

Posted by Derek

There's a lot of metabolic disease news this week from the FDA. We'll get to the inhaled insulin decision next week, but I thought I'd try to catch the next one before it happens. On Friday they're reviewing the first PPAR alpha-gamma ligand to make it to the regulatory approval stage, Bristol-Meyers Squibb's unmelodious "Pargluva" (muraglitazar), which sounds more like a disease than a drug. This is a therapeutic class that everyone had great hopes for a few years ago, with most of the big players competing at full speed. In theory, this combination should help with insulin sensitivity, cholesterol, and triglycerides all at the same time, which you'd think would be just what an overweight type II diabetic patient (and there are many) might need.

But development of these compounds has been a nightmare, with bad and unexpected toxicity cropping up deep in the late-phase work. BMS (and their late-arriving partner Merck) managed to get past those rapids and through clinical trials. But their drug shows a side effect that all PPAR-gamma drug programs have had to worry about, namely edema.

They also seem to have some (perhaps related) worries about cardiovascular events, which are broken out into completely separate categories in the FDA briefing document (big PDF). That document, whopper thought it is, is worth a look if you want to see what it's like to decide whether to approve a new drug or not. I wouldn't like to have to explain it all to a lay jury, that's for sure. No doubt a few whoops and hollers, along with the occasional choked tearful expression, would help.

By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . .

By the way, with thousands of people involved in the clinical studies, there are bound to be some. . .unplanned adverse events. I quote without comment from the briefing document linked to above, just in case you thought (for some odd reason) that running clinical trials was easy. . .

"Subject CV168021-29-21 was a 44-year old white maile with a 3-year history of diabetes and history of overweight, hypercholesterolemia and impotence. On study day 29 the subject died as the result of a gun shot wound.

Subject CV-168006-5-3 was a 62-year old white female with a history of hypertension, smoking, and alcohol use. On study day 112 she died in a motor vehicle accident. Her car was stopped at a light when struck by a truck. The investigator considered the event not likely related to study drug."

While its tempting to make summary statements regarding the deaths resulting form automobile accidents and gunshot wounds, the reality is that determining that these are not drug related is more difficult than one might initially imagine. For example, suicidal and other abnormal mental behaviors need to be excluded as possibly being drug induced.

True enough, but being hit by a truck while stopped at a light doesn't sound like impaired reflexes. Muraglitazar's structure makes it quite unlikely to penetrate the CNS, although I haven't seen the PK data on that yet.

Analyzing adverse event (AE) relatedness is one of those things that makes biostatisticians like me have their own AEs (usually something on the order of major seizure). On the one hand, there is the point of view that all relatedness data is BS and so all AEs are considered "related." Yes, even the gunshot wound and the auto accident, and the plane crash, meteors striking, whatever. Of course, there is an attempt to define relatedness in terms of when symptoms disappear and reappear (and removal of drug and rechallenge, ad nauseum). Despite this, there are some SOBs that will ignore relatedness data.

Now the real kicker is that the serious AEs come into the data entry system twice: once because of expedited reporting/safety committee monitoring and one because of standard, run of the mill case report form entries that are entered into the clinical database. And they'd better match, and this takes a lot of effort. And then when they come to us, something weird always falls out, so it's back and forth, back and forth. Because people's bodies do the darndest things. And when it's unplanned (always a bad thing in Phase III), you gotta file a safety update, unblind the patient's data (not a good thing), assess the impact of this on the probable conclusions and interpretations of the study's analysis, and on and on.

You oughtta pick up a book on clinical trials sometimes (like Fundamentals of Clinical Trials by Friedman et al.) sometime and look at the section on AEs. It starts not to look pretty, and actually working with the damned things is much much harder.